Project Summary ONC201 is a selective antagonist of the G-protein coupled receptor (GPCR) dopamine receptor domain 2 (DRD2) that is overexpressed in endometrial cancer (EC) due to its p53-independent control of the Akt/ERK signaling pathways. ONC201 is a first-in-class small molecule exhibits anticancer efficacy in a wide range of refractory cancers, including p53 mutant cells, by simultaneously inactivating Akt and ERK signaling, resulting in cell cycle arrest and apoptosis. Type II EC comprises non-endometrioid histology (i.e. serous, clear cell and mucinous) that are generally associated with more aggressive clinical behavior. This proposal supports a clinical trial of ONC201 in Type II EC patients with recurrent disease, who have mutations in p53 as well as deregulated Akt and ERK pathways in their tumors. In clinical trials, ONC201 has been exceptional well tolerated, possessed a therapeutic pharmacokinetic profile, and exhibited sustained pharmacodynamics and anti-cancer activity in advanced cancer patients. No > Grade 1 drug-related adverse events were observed in the first-in-human trial, despite achieving therapeutic blood levels and demonstrating signs of biological activity. Of the 28 evaluable patients in that trial, there were 5 advanced endometrial cancer patients and several exhibited clinical benefit and all expressed DRD2 in their archival tumor specimens. Among these heavily-pretreated 5 patients, the median number of prior treatments was 5 (3-6), 3 patients had prior radiation and all patients had prior surgery. After 2 doses of ONC201, one patient with clear cell EC had a mixed response with >50% decrease in lymphadenopathy. Two EC patients experienced prolonged stable disease lasting for 18 and 42 weeks, including a 56 year-old patient with serous- papillary EC who also had a significant and sustained reduction in the size of a metastatic lung lesion. Thus, EC emerged as the most promising tumor type from a preliminary efficacy perspective in this first-in-human trial in advanced solid tumors. Based on the clinical responses observed in this patient population, in this fast-track application we propose to first evaluate a pilot cohort of patients to evaluate the preliminary single agent efficacy profile in Type II EC patients. Depending on these clinical results, we will then conduct a larger study enrolling an additional 30 patients to determine the efficacy of ONC201 either as a single agent or in combination with paclitaxel. Phase/Aim#1: Evaluation of preliminary single agent efficacy profile in Type II EC patients. Phase/Aim #2: Determine the efficacy of ONC201 in Type II EC. This proposal seeks to provide a safe and durable treatment for patients with a disease that has few treatment options and a dismal prognosis.